Normal function against infectious agents is based on how the immune system achieves self/non-self discrimination, which remains a central conundrum in Immunology (1). What is “self” and what is “foreign”, as seen by the immune system, determines how the immune system discriminates self from non-self. In this regard, the pioneering work of Burnet and Medawar suggested that the definition of self versus non-self is arbitrary to the immune system because foreign antigens presented during fetal life are thereafter considered self (2, 3). Moreover, it is known that all T cells are self-referential in the sense that they are positively selected for survival on self-peptide/s bound to MHC molecules during thymic positive selection (4-7) before thymic negative selection, in which thymocytes expressing TCR of high avidity to the majority of self-antigens are deleted (8-10).
It is generally accepted that thymic negative selection eliminates the “imminent danger” of pathogenic autoimmunity in the periphery and is the major mechanism of self-tolerance. However, while releasing the “innocent” self-reactive T cells with low avidity, thymic negative selection also allows a large fraction of self-reactive T cells with “higher” or “intermediate” avidity to be released into the periphery under normal circumstances (11-13). The existence of the “intermediate avidity” self-reactive T cells in the periphery represents a “potential danger” of pathogenic auto-immunity inherited in each individual because these T cells can often be activated when they encounter self-peptides presented at a sufficient level and some may differentiate into potentially pathogenic effector cells to initiate an autoimmune disease (13-16). Self/non-self discrimination must continue in the periphery after thymic negative selection and one of the major functions of peripheral regulatory mechanisms is to selectively down-regulate immune responses to self-antigens without damaging the normal responses to foreign pathogens to maintain self-tolerance (17).
How does the immune system discriminate self from non-self in the periphery? Since self/non-self discrimination initiated during thymic negative selection is based on the avidity of thymocyte activation (8-10) and a large fraction of self-reactive T cells escape thymic negative selection (11-13), it is crucial to understand how the resultant peripheral T cell repertoire is regulated to complete self non-self discrimination initiated by thymic negative selection in order to maintain self-tolerance. In this regard, we have proposed and tested an “Avidity Model of Peripheral T Cell Regulation” in which self non-self discrimination can be achieved in the periphery via selective down-regulation of intermediate avidity T cells, to both self and foreign antigens, by Qa-1/HLA-E restricted CD8+ T cells (18, 19). Since the potentially pathogenic self-reactive T cells are included in the intermediate avidity T cell pool, selective down-regulation of intermediate avidity T cells can directly control autoimmune disease. On the other hand, the unified mechanism of selective down-regulation of intermediate avidity T cells does not inhibit immunity largely to foreign infectious agents or alloantigens mediated by high avidity T cells, simply because the high avidity T cells are not subject to this down-regulation. Thus, by a unified and simple mechanism, the immune system could accomplish self non-self discrimination in the periphery to specifically maintain self-tolerance without paying the price of dampening anti-infection and anti-tumor immunity.
The concept that perceiving the avidity of T cell activation can be translated into peripheral T cell regulation is the essence of the “Avidity Model”. The cellular mechanism that defines how perceiving the avidity of T cell activation is translated into peripheral T cell regulation and the molecular structures recognized by regulatory T cells that enable them to discriminate self from non-self in the periphery are the key issues of the regulatory T cell biology. In this regard a surrogate target structure (Qa-1/Hsp60sp) was recently identified which is specifically recognized by the Qa-1 restricted CD8+ T cells (1). The common surrogate target structure, the Qa-1/Hsp60sp complex, is only preferentially expressed at a higher level on the intermediate, but not high and low, avidity T cells, as a biological consequence of T cell activation (1). Thus, at a biological system level, by specific recognition of the common target structures expressed on the intermediate avidity T cells, the immune system is able to achieve the goal of self non-self discrimination in the periphery by perceiving the avidity of T cell activation.
The biggest difficulty in transplant medicine is the reaction of the immune system to the foreign organ, termed rejection. Conventionally, recipients of a transplanted organ must indefinitely take immunosuppressive medications to fight rejection, which are both prone to failure and leave the patient at high risk of infection. The invention disclosed herein provides a novel treatment strategy of inducing permanent tolerance of the transplanted organ without long term use of immunosuppressive drugs which incorporates the avidity model.